The trigger of arterial thrombosis inclusing acute coronary syndrome is platelet activation. However, the mechanism is largely unknown since it has been difficult to apply molecular biology on this research. To overcome the difficulty, we have developed assay systems for analyzing aggregation of granule secretion using platelets permeabilized with streptolysin-0 (Methods Enzymol. 2005, invited). We are investigating these mechanisms with these systems. In 2003, we directly demonstrated that PKCα is essential for the aggregation (JBC, 2003). In 2004, we demonstrated that an adaptor protein ShcA which binds to tyrosine-phophorylated β3 subunit of integrin, is essential for platelet aggregation (BBRC, 2004). We found that small GTPase Rab27 regulates dense-granule secretion (JBC, 2004). We further identified Munc13-4, a non-neuronal homologue of Munc13-1, an essential priming factor in neurotransmitter release, in platelet cytosol as a GTP-Rab27 binding protein using an affinity method and demonstrated that Munc1-4 regulates dense-granule secretion in platelets. This is the first indication that a RabGTPase directly regulates a member of Munc13. In collaboration with a Japanese research group investigating hemophagocytic syndrome, we found that approximately 30% of familial hemophagocytic syndrome is caused by mutation of Munc13-4 gene (FHL3) and that FHL3 patients reveals milder phenotype than patients caused by non-sense mutation of perforin (FHL2) (Blood, 2005).